STRUCTURAL BASIS OF CA2+-CALMODULIN-CALCINEURIN SIGNALLING

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 这些研究都不是专门针对艾滋病的，但这些研究旨在了解T细胞活化背后的蛋白质-蛋白质相互作用。 也有发表的证据表明，Ca 2 +-钙调蛋白-钙调磷酸酶途径有助于在潜伏感染细胞中重新激活卡波西肉瘤相关疱疹病毒。 这个子项目的总体目标是获得详细的结构和动力学信息的信号在钙离子-钙调蛋白-钙调磷酸酶途径。 钙调神经磷酸酶（CN）通过细胞微区的Ca 2+信号局部激活或通过广泛的细胞质Ca 2+信号全局激活，并通过使特定的磷酸丝氨酸或磷酸苏氨酸残基去磷酸化来控制其他细胞蛋白的活性。 CN在T细胞中具有突出的作用，其中它调节转录因子NFAT，从而调节细胞因子基因和与T细胞活化相关的其他基因的转录。 CN的这种作用是临床免疫抑制药物环孢素A和他克莫司的靶点。 CN还涉及发育过程，包括心脏瓣膜和血管系统的正确形成，以及病理生理变化，包括心肌肥大和损伤后血管再狭窄。 该项目涉及 (1)如何通过识别单个CN底物来引导CN信号传导; (2)如何通过与靶向和调节蛋白的相互作用来引导CN信号传导; (3)引发和维持CN活化的构象变化;以及 (4)构象变化和蛋白质-蛋白质相互作用的动力学，将细胞质Ca信号转化为CN信号。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. None of this research is specifically directed to AIDS, but the studies are directed toward understanding the protein-protein interactions underlying T cell activation. There is also published evidence that the Ca2+-calmodulin-calcineurin pathway contributes to reactivation of Kaposi sarcoma-associated herpesvirus in latently infected cells. The overall goal of this subproject is to obtain detailed structural and kinetic information on signalling in the Ca2+-calmodulin-calcineurin pathway. Calcineurin (CN) is activated either locally by Ca2+ signals in cellular microdomains or globally by widespread cytoplasmic Ca2+ signals, and controls the activity of other cellular proteins by dephosphorylating specific phosphoserine or phosphothreonine residues. CN has a prominent role in T cells, where it regulates the transcription factor NFAT and thereby the transcription of cytokine genes and other genes associated with T cell activation. This role of CN is the target of the clinical immunosuppressive drugs cyclosporin A and tacrolimus. CN is also implicated in developmental processes, including the proper formation of cardiac valves and the vascular system, and in pathophysiological changes, including myocardial hypertrophy and vascular restenosis after injury. This project addresses (1) how CN signalling is directed through recognition of individual CN substrates; (2) how CN signalling is directed through interaction with targeting and regulatory proteins; (3) the conformational changes that initiate and sustain CN activation; and (4) the kinetics of the conformational changes and protein-protein interactions that translate cytoplasmic Ca signals into CN signalling.